Chronic kidney disease--a common and serious complication after intestinal transplantation

BACKGROUND: Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with Chromium EDTA clearance. MATERIALS AND METHODS: Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation. RESULTS: Median baseline GFR was 67 (22-114) mL/min/1.73 m. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (n=5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR. CONCLUSION: Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.     

Metabolism studies of 4′Cl-CUMYL-PINACA, 4′F-CUMYL-5F-PINACA and 4′F-CUMYL-5F-PICA using human hepatocytes and LC-QTOF-MS analysis

4′Cl-cumyl-PINACA (SGT-157), 4′F-cumyl-5F-PINACA (4F-cumyl-5F-PINACA, SGT-65) and 4′F-cumyl-5F-PICA (4F-cumyl-5F-PICA, SGT-64) are a series of new halogenated cumyl synthetic cannabinoid receptor agonists (SCRAs). Due to rapid metabolism, monitoring and screening for SCRAs in biological matrices requires identification of their metabolites. It is an essential tool for estimating their spread and fluctuations in the global illicit market. The purpose of this study was to identify human biotransformations of 4′Cl-cumyl-PINACA, 4′F-cumyl-5F-PINACA and 4′F-cumyl-5F-PICA in vitro and characterize for the first time the metabolic pathways of halogenated cumyl SCRAs. 4′Cl-cumyl-PINACA, 4′F-cumyl-5F-PINACA and 4′F-cumyl-5F-PICA were incubated with human hepatocytes in duplicates for 0, 1, 3 and 5 h. The supernatants were analysed in data-dependent acquisition on a UHPLC-QToF-MS, and the potential metabolites were tentatively identified. A total of 11 metabolites were detected for 4′Cl-cumyl-PINACA, 21 for 4′F-cumyl-5F-PINACA and 10 for 4′F-cumyl-5F-PICA. The main biotransformations were oxidative defluorination, followed by hydroxylation with dehydrogenation, N-dealkylation, dihydrodiol formation and glucuronidation. Hydroxylations were most common at the tail moieties with higher abundancy for indole than indazole compounds. N-dealkylations were more common for fluorinated tail chain compounds than the non-fluorinated 4′Cl-cumyl-PINACA. In conclusion, many metabolites retained halogen groups at the cumyl moieties which, in various combinations, may be suitable as analytical biomarkers.     

Disclosing respiratory co-infections: a broad-range panel assay for avian respiratory pathogens on a nanofluidic PCR platform

Respiratory syndromes (RS) are among the most significant pathological conditions in edible birds and are caused by complex coactions of pathogens and environmental factors. In poultry, low pathogenic avian influenza A viruses, metapneumoviruses, infectious bronchitis virus, infectious laryngotracheitis virus, Mycoplasma spp. Escherichia coli and/or Ornithobacterium rhinotracheale in turkeys are considered as key co-infectious agents of RS. Aspergillus sp., Pasteurella multocida, Avibacterium paragallinarum or Chlamydia psittaci may also be involved in respiratory outbreaks. An innovative quantitative PCR method, based on a nanofluidic technology, has the ability to screen up to 96 samples with 96 pathogen-specific PCR primers, at the same time, in one run of real-time quantitative PCR. This platform was used for the screening of avian respiratory pathogens: 15 respiratory agents, including viruses, bacteria and fungi potentially associated with respiratory infections of poultry, were targeted. Primers were designed and validated for SYBR green real-time quantitative PCR and subsequently validated on the Biomark high throughput PCR nanofluidic platform (Fluidigm©, San Francisco, CA, USA). As a clinical assessment, tracheal swabs were sampled from turkeys showing RS and submitted to this panel assay. Beside systematic detection of E. coli, avian metapneumovirus, Mycoplasma gallisepticum and Mycoplasma synoviae were frequently detected, with distinctive co-infection patterns between French and Moroccan flocks. This proof-of-concept study illustrates the potential of such panel assays for unveiling respiratory co-infection profiles in poultry.     

MEFV and NLRP3 Inflammasome Expression Is Attributed to Immature Macrophages and Correlates with Serum Inflammatory Proteins in Crohn´s Disease Patients

Inflammation - Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet...     

Clinical assessment and comparison of annotation algorithms in high‐density mapping of regular atrial tachycardias

1 Background

High‐density automated mapping of regular atrial tachycardias (ATs) requires accurate assessment of local activation times (LATs).

2 Objective

To evaluate high‐density mapping of ATs and compare the accuracy of different automated LAT annotation algorithms.

3 Methods

Fifteen patients underwent AT ablation guided by the automated ConfiDENSE? high‐density mapping module (Carto 3 v4) allowing manual reannotation (edited maps). For each AT, unedited automated maps were reconstructed offline by three algorithms: maximum unipolar slope (LAT_Slope), bipolar peak (LAT_Peak), and a new hybrid annotation algorithm (LAT_Hybrid). Five blinded experts were asked to define the (1) tachycardia mechanism, (2) ablation target, and (3) level of difficulty of these unedited maps.

4 Results

Twenty‐one ATs (cycle length 300 ± 46 ms, activation points 955 ± 421) were successfully ablated using LAT_Hybrid guided ablation with manual editing in a small number of points. At 6 months, 14 (93%) of the patients were free of AT recurrences. Unedited LAT_Hybrid maps showed the highest accuracy in defining the tachycardia mechanism (LAT_Hybrid: 49% vs. LAT_Peak: 27% vs. LAT_Slope: 28%, P < 0.001) and ablation target (LAT_Hybrid: 65% vs. LAT_Peak: 39% vs. LAT_Slope: 31%, P < 0.001). Overall, LAT_Hybrid‐annotated maps were graded as “easier to interpret” by the experts (difficulty score 2.3 ± 0.9) versus LAT_Peak (2.8 ± 1) and LAT_Slope (3.2 ± 0.8) (P < 0.001). Only 12% of the LAT_Hybrid maps were annotated as uninterpretable compared to 31% of LAT_Slope and 45% of the LAT_Peak maps (P < 0.001).

5 Conclusion

Automated LAT_Hybrid annotation allows better and easier recognition of the tachycardia mechanism compared to automated LAT_Peak and LAT_Slope algorithms, although fully automated mapping still requires further improvements.     

Predictive Value of DXA Appendicular Lean Mass for Incident Fractures,Falls, and Mortality,Independent of Prior Falls,FRAX, and BMD: Findings from the Women's Health Initiative (WHI)

In the Women's Health Initiative (WHI), we investigated associations between baseline dual-energy X-ray absorptiometry (DXA) appendicular lean mass (ALM) and risk of incident fractures, falls, and mortality (separately for each outcome) among older postmenopausal women, accounting for bone mineral density (BMD), prior falls, and Fracture Risk Assessment Tool (FRAX^®) probability. The WHI is a prospective study of postmenopausal women undertaken at 40 US sites. We used an extension of Poisson regression to investigate the relationship between baseline ALM (corrected for height²) and incident fracture outcomes, presented here for major osteoporotic fracture (MOF: hip, clinical vertebral, forearm, or proximal humerus), falls, and death. Associations were adjusted for age, time since baseline and randomization group, or additionally for femoral neck (FN) BMD, prior falls, or FRAX probability (MOF without BMD) and are reported as gradient of risk (GR: hazard ratio for first incident fracture per SD increment) in ALM/height² (GR). Data were available for 11,187 women (mean [SD] age 63.3 [7.4] years). In the base models (adjusted for age, follow-up time, and randomization group), greater ALM/height² was associated with lower risk of incident MOF (GR = 0.88; 95% confidence interval [CI] 0.83–0.94). The association was independent of prior falls but was attenuated by FRAX probability. Adjustment for FN BMD T-score led to attenuation and inversion of the risk relationship (GR = 1.06; 95% CI 0.98–1.14). There were no associations between ALM/height² and incident falls. However, there was a 7% to 15% increase in risk of death during follow-up for each SD greater ALM/height², depending on specific adjustment. In WHI, and consistent with our findings in older men (Osteoporotic Fractures in Men [MrOS] study cohorts), the predictive value of DXA-ALM for future clinical fracture is attenuated (and potentially inverted) after adjustment for femoral neck BMD T-score. However, intriguing positive, but modest, associations between ALM/height² and mortality remain robust. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).